Thrombocytopenia is a disease in which platelet destruction is promoted or platelets are insufficiently produced, causing a reduction in the number of platelets and resulting in bleeding tendency. Hemorrhagic events include brain hemorrhage, internal hemorrhage, petechia, purpura, mucosal hemorrhages (nasal hemorrhage, gastrointestinal hemorrhage, genital hemorrhage) and the like, and in some cases, excessive bleeding may be observed after surgery.
It is known that one of the causes of thrombocytopenia is chronic liver disease. In chronic liver disease patients, a decrease in hepatic spare ability with the development of disease stages, and a decrease in the platelet count with hypersplenism are observed. Most of chronic hepatitis is caused by hepatitis B or C virus infection, of which hepatitis C virus infection is predominant. Hepatitis C tends to become chronic and is developed to liver cirrhosis and further to hepatocellular carcinoma, causing about 34,000 deaths annually. Upon treatment for hepatitis or liver cancer, patients with thrombocytopenia may not be able to receive anti-virus therapy using interferons or may require splenectomy, partial splenic embolization (PSE) or platelet transfusion when undergoing invasive procedures such as laparotomy and local therapy.
However, these procedures have the following problems, and thus are not always safe and convenient:    splenectomy is highly invasive and is reported to cause portal vein thrombosis and decrease immunocompetence;    PSE is reported to cause splenic abscess and sepsis;    platelet transfusion has risks of transfusion-related side effects (transfusion-related acute lung injury and infection), and platelet products have a short expiration date (4 days after blood collection). It is also known that repeated platelet transfusion may promote antibody production, causing platelet transfusion refractoriness.
Under these circumstances, there is a need for a therapeutic agent for thrombocytopenia that has no side effect and can be readily administered.
Thrombopoietin (TPO) is a cytokine that acts on hematopoietic stem cells/megakaryocyte progenitor cells to promote proliferation and differentiation to megakaryocytes and production of platelets. A recombinant human TPO was previously studied in a clinical trial. However, it induced a neutralizing antibody directed to endogenous TPO, and thus the development thereof was stopped due to antigenicity. Among cytokines having activity on production of platelets in megakaryocytes, only an injection containing interleukin 11 is clinically applied in the United States. However, the approved indication thereof is limited to improvement of thrombocytopenia caused by bone-marrow suppression after chemotherapy because of side effects including fluid accumulation, palpitation, edema and the like.
A nucleotide sequence of a gene encoding the thrombopoietin receptor is disclosed in Non-Patent Document 1.
Under these circumstances, compounds having a thrombopoietin receptor agonistic activity are expected as therapeutic agents for thrombocytopenia that can replace the present therapies and treatments including platelet transfusion. As therapeutic agents for chronic immune thrombocytopenia (chronic ITP), romiplostim which is an injectable thrombopoietin mimetic peptide and eltrombopag which is a low molecular TPO receptor agonist are currently approved in the United States and Europe.
Patent Document 1 discloses, as a compound having a thrombopoietin receptor agonistic activity,    (E)-3-[2,6-dichloro-4-[4-[3-[(S)-1-hexyloxyethyl]-2-methoxyphenyl]-thiazol-2-ylcarbamoyl]-phenyl]-2-methylacrylic acid.
Eltrombopag, a low molecular compound having a thrombopoietin receptor agonistic activity, was studied in a clinical trial abroad designed to administer the investigational drug for 2 weeks before the invasive procedures to chronic liver disease patients who were scheduled to undergo invasive procedures and had a platelet count of less than 5×104/μL and the Child-Pugh score of 12 or less. The results showed that an avoidance of platelet transfusion, an efficacy endpoint, was higher in the active drug group than in the placebo group (placebo group: 19%, active drug group: 72%). However, the incidence of portal vein thrombosis was higher in the active drug group than in the placebo group (placebo group: 1%, active drug group: 4%). It is reported in Non-Patent Document 2 that most cases of portal vein thrombosis were developed after invasive procedures carried out after termination of administration of the investigational drug and that the platelet count in 5 cases out of 6 in the active drug group was 20×104/μL or higher at the time of the development of portal vein thrombosis. With regard to the correlation between the risk of development of portal vein thrombosis and the platelet count, the risk in the group having the platelet count of 20×104/μL or higher during the investigation period was about 9 times higher than the risk in the group with the platelet count of less than 20×104/μL (10.6% vs. 1.2%). Thus it is suggested that an increase in the platelet count in patients having thrombocytopenia resulting from development of chronic hepatitis to 20×104/μL or higher may increase the risk of onset of portal vein thrombosis.
Compounds having a thrombopoietin receptor agonistic activity, eltrombopag and romiplostim, have already been launched for the indication of “chronic idiopathic thrombocytopenic purpura”. The administration discontinuating criteria of the drugs upon excessive increase in the platelet count indicated in the package inserts of the drugs (Non-Patent Document 3 and 4) is “stop the drug if the platelet count exceeds 400,000/μL”.